Dual antiplatelet/anticoagulant pyridoxine analogs

a technology of pyridoxine and antiplatelet, which is applied in the field of pyridoxine analogs, can solve the problems of inappropriate reaction initiation and propagation

Inactive Publication Date: 2006-05-04
MEDICURE INT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] One embodiment of the invention includes pyridoxine analogs, particularly bis-amidine pyridoxine analogs, and methods of treatment using therapeutically effective amounts of the pyridoxines. Another embodiment of the invention includes substituted bis-amidine pyridoxine analogs, compositions containing substituted pyridoxine analogs, and methods of treatment using therapeutically effective amounts of substituted bis-amidine pyridoxine analogs. Compounds and compositions of the invention are both antiplatelet and anticoagulant, and thus can be used to treat cardiovascular, cerebrovascular, or related diseases and symptoms thereof.

Problems solved by technology

The pathways involved normally inhibit blood loss after vessel injury, but in thrombosis and related conditions, these reactions are inappropriately initiated and propagated.

Method used

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  • Dual antiplatelet/anticoagulant pyridoxine analogs
  • Dual antiplatelet/anticoagulant pyridoxine analogs
  • Dual antiplatelet/anticoagulant pyridoxine analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 4-{[3-(4-Cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-amino}-benzonitrile (2)

[0309]

[0310] A mixture of 4-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-benzonitrile (1)* (404 mg, 1.5 mmol), α-bromo-p-tolunitrile (322 mg, 1.65 mmol), potassium carbonate (622 mg, 4.5 mmol) and DMF (10 mL) was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was evaporated to dryness, and the crude product purified by column chromatography on silica gel using a gradient of dichloromethane:methyl alcohol (9:1) as eluant to give 4-{[3-(3-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-amino}-benzonitrile (2) (348 mg, 60% yield) as a colorless solid.

[0311]1H-NMR (DMSO-d6): δ 8.32 (s, 1H), 7.83-7.74 (m, 3H), 7.56 (t, 1H), 7.44 (d, 2H), 6.76 (t, 1H), 6.69 (d, 2H), 5.32 (s, 1H), 4.95 (s, 2H), 4.59 (s, 2H), 4.31 (d, 2H), 2.47 (s, 3H).

*U.S. Pat. No. 6,417,204B1(2002)

example 2

Synthesis of 4-{[3-(4-Carbamimidoyl-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-amino}-benzamidine (3)

[0312]

[0313] Hydrogen chloride gas was bubbled into a suspension of 4-{[3-(4-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-amino}-benzonitrile (2) (102 mg, 0.265 mmol) in absolute ethyl alcohol (100 mL) at room temperature for 30 minutes. The septum was replaced and the reaction mixture was stirred for overnight at room temperature. The reaction mixture was purged with nitrogen gas for 2 hours to remove excess hydrogen chloride and the solvent evaporated to give the crude imino ester as a solid. Ammonia in methyl alcohol (10 mL, 7M, 70 mmol) was then added to the crude amide ester and stirred overnight at room temperature. The solvent was evaporated and the product purified on a silica gel column using a mixture of water:methyl alcohol:chloroform (1:10:20) as eluant to give the corresponding 4-{[3-(4-carbamimidoyl-benzyloxy)-5-hydroxymethyl-2-methyl-pyri...

example 3

Synthesis of 4′-{[5-(4-Cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-4-carbonitrile (4)

[0316]

[0317] A mixture of 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphenyl-4-carbonitrile (4) (691 mg, 2.0 mmol), α-bromo-p-tolunitrile (392 mg, 2.0 mmol), cesium carbonate (1303 mg, 4.0 mmol) and DMF (20 mL) was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was evaporated to dryness, and the crude product purified by column chromatography on silica gel using a gradient of dichloromethane:methyl alcohol (20:1) as eluant to give product 4′-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-4-carbonitrile (5) (513 mg, 56% yield).

[0318]1H-NMR (DMSO-d6): δ 8.22 (s, 1H), 7.92 (d, 2H), 7.81-7.71 (m, 6H), 7.54 (d, 2H), 6.73 (d, 2H), 6.54 (t, 1H), 5.32 (t, 1H), 5.04 (s, 2H), 4.65 (d, 2H), 4.50 (d, 2H), 2.42 (s, 3H).

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Abstract

Compounds with antiplatelet aggregation and anticoagulant characteristics for the treatment of cardiovascular, cerebrovascular, and cardiovascular related diseases and symptoms, are described. The methods are directed to administering pharmaceutical compositions comprising aryl sulfonic pyridoxine and/or substituted pyridoxine analogs.

Description

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60 / 622,627, filed Oct. 28, 2004, the entire disclosure of which is hereby incorporated by reference.FIELD OF THE INVENTION [0002] This invention relates to pyridoxine analogs and methods of treating cardiovascular, cerebrovascular, and cardiovascular related diseases or symptoms by administering pharmaceutical compositions comprising pyridoxine analogs to inhibit coagulation and platelet aggregation. BACKGROUND [0003] Thrombosis, the development of blood clots within arterial vessels, is due to a complex mechanism involving the activation of both platelet aggregation and the coagulation protease cascade (Ann. Intern Med. (2001) 134: 224-38; N. Engl. J. Med. (2002) 347: 5-12; Thromb. Haemost. (2002) 86: 51-6). The pathways involved normally inhibit blood loss after vessel injury, but in thrombosis and related conditions, these reactions are inappropriately initiated and propagated....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/02C07D213/63A61K31/444A61K31/44
CPCC07D213/65C07D213/66C07D213/74C07D213/79C07D213/80C07D213/81C07D213/89C07D491/04C07D498/04A61P43/00A61P7/02A61P9/00
Inventor HAQUE, WASIMULDIAKUR, JAMESPHAM, VINHREHMAN, ATIQWHITNEY, TARAOMAR, MOHAMMEDYI, SENGKHAN, A.
Owner MEDICURE INT INC
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